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Low Nonrelapse Mortality after HLA-Matched Related 2-Step Hematopoietic Stem Cell Transplantation Using Cyclophosphamide for Graft-versus-Host Disease Prophylaxis and the Potential Impact of Non- Cyclophosphamide-Exposed T Cells on Outcomes.
Biol Blood Marrow Transplant. 2020 Jul 03 [Online ahead of print]BB

Abstract

The use of cyclophosphamide (CY) for bidirectional tolerization of recipient and donor T cells is associated with reduced rates of graft-versus-host disease (GVHD) and nonrelapse mortality (NRM) after HLA-matched hematopoietic stem cell transplantation (HSCT). However, recurrent disease remains the primary barrier to long-term survival. We extended our 2-step approach to HLA-matched related HSCT using a radiation-based myeloablative conditioning regimen combined with a high dose of T cells in an attempt to reduce relapse rates while maintaining the beneficial effects of CY tolerization. After conditioning, patients received their grafts in 2 components: (1) a fixed dose of 2 × 108/kg T cells, followed 2 days later by CY, and (2) a CD34-selected graft containing a small residual amount of non-CY-exposed T cells, at a median dose of 2.98 × 103/kg. Forty-six patients with hematologic malignancies were treated. Despite the myeloablative conditioning regimen and use of high T cell doses, the cumulative incidences of grade II-IV acute GVHD, chronic GVHD, and NRM at 1 year and 5 years were very low, at 13%, 9%, and 4.3%, respectively. This contributed to a high overall survival of 89.1% at 1 year and 65.8% at 5 years. Relapse was the primary cause of mortality, with a cumulative incidence of 23.9% at 1 year and 45.7% at 5 years. In a post hoc analysis, relapse rates were significantly lower in patients receiving greater than versus those receiving less than the group median of non-CY-exposed residual T cells in the CD34 product (19.3% versus 58.1%; P = .009), without a concomitant increase in NRM. In its current form, this 2-step regimen was highly tolerable, but strategies to reduce relapse, potentially the addition of T cells not exposed to CY, are needed.

Authors+Show Affiliations

Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. Electronic address: lorigrosso@gmail.com.Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.Blood and Marrow Transplant Cell Processing Lab, Thomas Jefferson University, Philadelphia, Pennsylvania.Department of Pathology, Tissue Typing, Thomas Jefferson University, Philadelphia, Pennsylvania.Department of Radiation Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.Department of Radiation Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.Clinical Research Office, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32629157

Citation

Grosso, Dolores, et al. "Low Nonrelapse Mortality After HLA-Matched Related 2-Step Hematopoietic Stem Cell Transplantation Using Cyclophosphamide for Graft-versus-Host Disease Prophylaxis and the Potential Impact of Non- Cyclophosphamide-Exposed T Cells On Outcomes." Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation, 2020.
Grosso D, Carabasi M, Filicko-O'Hara J, et al. Low Nonrelapse Mortality after HLA-Matched Related 2-Step Hematopoietic Stem Cell Transplantation Using Cyclophosphamide for Graft-versus-Host Disease Prophylaxis and the Potential Impact of Non- Cyclophosphamide-Exposed T Cells on Outcomes. Biol Blood Marrow Transplant. 2020.
Grosso, D., Carabasi, M., Filicko-O'Hara, J., Wagner, J. L., O'Hara, W., Sun, M., Colombe, B., Shi, W., Werner-Wasik, M., Rudolph, S., Alpdogan, O., Binder, A., Kasner, M., Klumpp, T., Martinez-Outschoorn, U., Palmisiano, N., Wilde, L., Porcu, P., Gergis, U., & Flomenberg, N. (2020). Low Nonrelapse Mortality after HLA-Matched Related 2-Step Hematopoietic Stem Cell Transplantation Using Cyclophosphamide for Graft-versus-Host Disease Prophylaxis and the Potential Impact of Non- Cyclophosphamide-Exposed T Cells on Outcomes. Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. https://doi.org/10.1016/j.bbmt.2020.06.021
Grosso D, et al. Low Nonrelapse Mortality After HLA-Matched Related 2-Step Hematopoietic Stem Cell Transplantation Using Cyclophosphamide for Graft-versus-Host Disease Prophylaxis and the Potential Impact of Non- Cyclophosphamide-Exposed T Cells On Outcomes. Biol Blood Marrow Transplant. 2020 Jul 3; PubMed PMID: 32629157.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Low Nonrelapse Mortality after HLA-Matched Related 2-Step Hematopoietic Stem Cell Transplantation Using Cyclophosphamide for Graft-versus-Host Disease Prophylaxis and the Potential Impact of Non- Cyclophosphamide-Exposed T Cells on Outcomes. AU - Grosso,Dolores, AU - Carabasi,Matthew, AU - Filicko-O'Hara,Joanne, AU - Wagner,John L, AU - O'Hara,William, AU - Sun,Michael, AU - Colombe,Beth, AU - Shi,W, AU - Werner-Wasik,Maria, AU - Rudolph,Shannon, AU - Alpdogan,Onder, AU - Binder,Adam, AU - Kasner,Margaret, AU - Klumpp,Thomas, AU - Martinez-Outschoorn,Ubaldo, AU - Palmisiano,Neil, AU - Wilde,Lindsay, AU - Porcu,Pierluigi, AU - Gergis,Usama, AU - Flomenberg,Neal, Y1 - 2020/07/03/ PY - 2020/05/04/received PY - 2020/06/12/revised PY - 2020/06/24/accepted PY - 2020/7/7/pubmed PY - 2020/7/7/medline PY - 2020/7/7/entrez KW - Cyclophosphamide tolerization KW - Low nonrelapse mortality KW - Matched related KW - Strategies to decrease relapse KW - Two-step approach KW - Untolerized T cells JF - Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation JO - Biol. Blood Marrow Transplant. N2 - The use of cyclophosphamide (CY) for bidirectional tolerization of recipient and donor T cells is associated with reduced rates of graft-versus-host disease (GVHD) and nonrelapse mortality (NRM) after HLA-matched hematopoietic stem cell transplantation (HSCT). However, recurrent disease remains the primary barrier to long-term survival. We extended our 2-step approach to HLA-matched related HSCT using a radiation-based myeloablative conditioning regimen combined with a high dose of T cells in an attempt to reduce relapse rates while maintaining the beneficial effects of CY tolerization. After conditioning, patients received their grafts in 2 components: (1) a fixed dose of 2 × 108/kg T cells, followed 2 days later by CY, and (2) a CD34-selected graft containing a small residual amount of non-CY-exposed T cells, at a median dose of 2.98 × 103/kg. Forty-six patients with hematologic malignancies were treated. Despite the myeloablative conditioning regimen and use of high T cell doses, the cumulative incidences of grade II-IV acute GVHD, chronic GVHD, and NRM at 1 year and 5 years were very low, at 13%, 9%, and 4.3%, respectively. This contributed to a high overall survival of 89.1% at 1 year and 65.8% at 5 years. Relapse was the primary cause of mortality, with a cumulative incidence of 23.9% at 1 year and 45.7% at 5 years. In a post hoc analysis, relapse rates were significantly lower in patients receiving greater than versus those receiving less than the group median of non-CY-exposed residual T cells in the CD34 product (19.3% versus 58.1%; P = .009), without a concomitant increase in NRM. In its current form, this 2-step regimen was highly tolerable, but strategies to reduce relapse, potentially the addition of T cells not exposed to CY, are needed. SN - 1523-6536 UR - https://www.unboundmedicine.com/medline/citation/32629157/Low_Non-Relapse_Mortality_after_HLA_Matched_Related_Two-Step_Hematopoietic_Stem_Cell_Transplantation_using_Cyclophosphamide_(CY)_for_Graft_versus_Host_Disease_Prophylaxis_and_the_Potential_Impact_of_Non-CY-Exposed_T_Cells_on_Outcomes L2 - https://linkinghub.elsevier.com/retrieve/pii/S1083-8791(20)30396-7 DB - PRIME DP - Unbound Medicine ER -
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